The objectives of the proposed research are to develop therapeutic drug regimens that will have use in the treatment of cancer in man on the basis of pharmacological and biochemical information on the mechanism of drug action, with particular emphasis on (a) characterization of the metabolic alterations responsible for cell death following exposure to chemical stress, (b) exploitation of possible neoplastic cellular sites of vulnerability by chemical modification of existing agents having some clinical efficacy, as well as further design and synthesis of new drugs based upon biochemical and pharmacological principles, and (c) the selection, on the basis of metabolic action of drugs to employ in combination, thereby gaining increased therapeutic efficacy. Research emphasis is being placed upon the following: (a) gamma-(N)-heterocyclic carboxaldehyde thiosemicarbazones, in an effort to develop a second generation inhibitor of ribonucleotide reductase with clinical potential, and the importance of inhibition of pyrimidine nucleoside kinase and RNA synthesis by these agents; (b) quinone derivatives which function as bioreductive alkylating agents; (c) tetramisole derivatives as inhibitors of alkaline phosphohydrolase; (d) development of aryl sulfonyl hydrazones of pyridine N-oxides as anticancer drugs; and (e) effects of anticancer agents and other metabolic inhibitors on surface membranes of neoplastic cells. BIBLIOGRAPHIC REFERENCES: Lin, A. J., and Sartorelli, A. C., Potential Bioreductive Alkylating Agents. 6. Determination of the Relationship Between Oxidation-Reduction Potential and Antineoplastic Activity. Biochemical Pharmacol. 25: 206-207 (1976). Agrawal, K. C., Clayman, S., and Sartorelli, A. C., Synthesis of Site-Directed Chelating Agents. II: 2-Formy1-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone. J. Pharmaceut. Sci., 65: 297-300 (1976).